Non-imidazole heterocyclic compounds

ABSTRACT

Certain non-imidazole heterocyclic compounds are histamine H 3  modulators useful in the treatment of histamine H 3  receptor mediated diseases.

FIELD OF THE INVENTION

The present invention relates to a series of thiophenes, furans,pyrroles, thiazoles, and oxazoles, their synthesis and their use, forexample, for the treatment of disorders and conditions mediated by thehistamine H₃ receptor.

BACKGROUND OF THE INVENTION

Histamine {2-(imidazol-4-yl)ethylamine} is a transmitter substance.Histamine exerts a physiological effect via multiple distinct G-proteincoupled receptors. It plays a role in immediate hypersensitivityreactions and is released from mast cells following antigen IgE antibodyinteraction. The actions of released histamine on the vasculature andsmooth muscle system account for the symptoms of the allergic response.These actions occur at the H₁ receptor (Ash, A. S. F. and Schild, H. O.,Br. J. Pharmac. Chemother. 1966, 27:427-439) and are blocked by theclassical antihistamines (e.g. diphenhydramine). Histamine is also animportant regulator of gastric acid secretion through its action onparietal cells. These effects of histamine are mediated via the H₂receptor (Black, J. W. et al., Nature 1972, 236:385-390) and are blockedby H₂ receptor antagonists (e.g. cimetidine). The third histaminereceptor —H₃— was first described as a presynaptic autoreceptor in thecentral nervous system (CNS) (Arrang, J.-M. et al., Nature 1983,302:832-837) controlling the synthesis and release of histamine. Recentevidence has emerged showing that H₃ receptors are also locatedpresynaptically as heteroreceptors on serotonergic, noradrenergic,dopaminergic, cholinergic, and GABAergic (gamma-aminobutyric acidcontaining) neurons. These H₃ receptors have also recently beenidentified in peripheral tissues such as vascular smooth muscle.Consequently, there are many potential therapeutic applications forhistamine H₃ agonists, antagonists, and inverse agonists. (See: “TheHistamine H₃ Receptor-A Target for New Drugs”, Leurs, R., and Timmerman,H., (Eds.), Elsevier, 1998; Morisset, S. et al., Nature 2000,408:860-864.) A fourth histamine receptor —H₄— was recently described byOda, T. et al. (J. Biol. Chem. 2000, 275(47):36781-36786).

The potential use of histamine H₃ agonists in sleep/wake andarousal/vigilance disorders is suggested based on animal studies (Lin,J.-S. et al., Brain Res. 1990, 523:325-330; Monti, J. M. et al., Eur. J.Pharmacol. 1991, 205:283-287). Their use in the treatment of migrainehas also been suggested (McLeod, R. L. et al., Soc. Neurosci. Abstr.1996, 22:2010) based on their ability to inhibit neurogenicinflammation. Other applications could include a protective role inmyocardial ischemia and hypertension where blockade of norepinephrinerelease is beneficial (Imamura, M. et al., J. Pharmacol. Exp. Ther.1994, 271(3):1259-1266). It has been suggested that histamine H₃agonists may be beneficial in asthma due to their ability to reducenon-adrenergic non-cholinergic (NANC) neurotransmission in airways andto reduce microvascular leakage (Ichinose, M. and Barnes, P. J., Eur. J.Pharmacol. 1989, 174:49-55).

Several indications for histamine H₃ antagonists and inverse agonistshave similarly been proposed based on animal pharmacology experimentswith known histamine H₃ antagonists (e.g. thioperamide). These includedementia, Alzheimer's disease (Panula, P. et al., Soc. Neurosci. Abstr.1995, 21:1977), epilepsy (Yokoyama, H. et al., Eur. J. Pharmacol. 1993,234:129-133), narcolepsy with or without associated cataplexy,cataplexy, disorders of sleep/wake homeostasis, idiopathic somnolence,excessive daytime sleepiness (EDS), circadian rhythm disorders,sleep/fatigue disorders, fatigue, drowsiness associated with sleepapnea, sleep impairment due to perimenopausal hormonal shifts, jet lag,Parkinson's-related fatigue, multiple sclerosis (MS)-related fatigue,depression-related fatigue, chemotherapy-induced fatigue, eatingdisorders (Machidori, H. et al., Brain Res. 1992, 590:180-186), motionsickness, vertigo, attention deficit hyperactivity disorders (ADHD),learning and memory (Barnes, J. C. et al., Soc. Neurosci. Abstr. 1993,19:1813), and schizophrenia (Schlicker, E. and Marr, I.,Naunyn-Schmiedeberg's Arch. Pharmacol. 1996, 353:290-294). (Also see:Stark, H. et al., Drugs Future 1996, 21(5):507-520; and Leurs, R. etal., Prog. Drug Res. 1995, 45:107-165 and references cited therein.)Histamine H₃ antagonists, alone or in combination with a histamine H₁antagonist, are reported to be useful for the treatment of upper airwayallergic response (U.S. Pat. Nos. 5,217,986; 5,352,707 and 5,869,479).Recently, a histamine H₃ antagonist (GT-2331) was identified and isbeing developed by Gliatech Inc. (Gliatech Inc. Press Release Nov. 5,1998; Bioworld Today, Mar. 2, 1999) for the treatment of CNS disorders.

As noted, the literature related to histamine H₃ ligands has beencomprehensively reviewed (“The Histamine H₃ Receptor—A Target for NewDrugs”, Leurs, R. and Timmerman, H., (Eds.), Elsevier, 1998). Withinthis reference the medicinal chemistry of histamine H₃ agonists andantagonists was reviewed (see Krause, M. et al., and Phillips, J. G. andAli, S. M., respectively). The importance of an imidazole moietycontaining only a single substitution in the 4-position was noted,together with the deleterious effects of additional substitution onactivity. Particularly, methylation of the imidazole ring at any of theremaining unsubstituted positions was reported to strongly decreaseactivity. Additional publications support the hypothesis that animidazole function is essential for high affinity histamine H₃ receptorligands (see Ali, S. M. et al., J. Med. Chem. 1999, 42:903-909, andStark, H. et al., and references cited therein). However, manyimidazole-containing compounds are substrates for histamine methyltransferase, the major histamine metabolizing enzyme in humans, whichleads to shortened half-lives and lower bioavailability (see Rouleau, A.et al., J. Pharmacol. Exp. Ther. 1997, 281(3):1085-1094). In addition,imidazole-containing drugs, via their interaction with the cytochromeP₄₅₀ monooxygenase system, can participate in unfavorablebiotransformations due to enzyme induction or enzyme inhibition (see:Kapetanovic, I. M. and Kupferberg, H. J., Drug Metab. Dispos. 1984,12(5):560-564; Sheets, J. J. and Mason, J. I., Drug Metab. Dispos. 1984,12(5):603-606; Back, D. J. and Tjia, J. F., Br. J. Pharmacol. 1985,85:121-126; Lavrijsen, K. et al., Biochem. Pharmacol. 1986,35(11):1867-1878; Albengres, E. et al., Drug Safety 1998, 18(2):83-97).The poor blood brain barrier penetration of earlier histamine H₃receptor ligands may also be associated with the imidazole fragment(Ganellin, C. R. et al., Arch. Pharm. Pharm. Med. Chem. (Weinheim, Ger.)1998, 331:395-404).

More recently, several publications have described histamine H₃ ligandsthat do not contain an imidazole moiety, for example: Ganellin, C. R. etal.; Walczynski, K. et al., Arch. Pharm. Pharm. Med. Chem. (Weinheim,Ger.) 1999, 332:389-398; Walczynski, K. et al., Farmaco 1999,54:684-694; Linney, I. D. et al., J. Med. Chem. 2000, 43:2362-2370;Tozer, M. J. and Kalindjian, S. B., Exp. Opin. Ther. Patents 2000,10:1045-1055; U.S. Pat. No. 5,352,707; PCT Application WO 99/42458, Aug.26, 1999; PCT Application WO 02/076925; and European Patent Application0978512, Feb. 9, 2000.

In addition, a more recent review of this topic was presented (Tozer, M.T. and Kalindjian, S. B. Exp. Opin. Ther. Patents 2000, 10:1045).Additional publications and patents, concerning both histamine H₃agonists and antagonists, have appeared since the publication of theLeurs monograph. Most noteworthy is the development of non-imidazolehistamine H₃ antagonists (Apodaca et al WO 02/12214; Apodaca et al WO02/12190; Bogenstaetter et al 02/12224; Carruthers et al WO 01/74810;Chai et al WO 01/74814; Breitenbucher et al WO 01/74815; Breitenbucheret al WO 01/74813; Breitenbucher et al WO 01/74773; Bennani et al WO02/06223; Bennani et al WO 01/66534; Schwartz et al EP 0978512 A1;Schwartz et al WO 00/06254; Linney et al J. Med. Chem. 2000, 43, 2362;and Ganellin et al Arch. Pharm. Pharm. Med. Chem. 1998, 331, 395).

The compounds of the present invention do not contain the imidazolemoiety, and its inherent liabilities, and yet maintain potency at thehuman H₃ receptor as determined by receptor binding to the humanhistamine H₃ receptor (see Lovenberg, T. W. et al., Mol. Pharmacol.1999, 55:1101-1107). Screening using the human receptor is particularlyimportant for the identification of new therapies for the treatment ofhuman disease. Conventional binding assays, for example, are determinedusing rat synaptosomes (Garbarg, M. et al., J. Pharmacol. Exp. Ther.1992, 263(1):304-310), rat cortical membranes (West, R. E. et al., Mol.Pharmacol. 1990, 38:610-613), and guinea pig brain (Korte, A. et al.,Biochem. Biophys. Res. Commun. 1990, 168(3):979-986). Only limitedstudies have been performed previously using human tissue but theseallude to significant differences in the pharmacology of rodent andprimate receptors (West, R. E. et al., Eur. J. Pharmacol. 1999,377:233-239).

Described herein is a series of 5-membered aromatic heterocycliccompounds with the ability to modulate the activity of the histaminereceptor, specifically the H₃ receptor, without the inherent problemsassociated with the presence of an imidazole moiety.

SUMMARY OF THE INVENTION

The invention features a heterocyclic compound of formula (I):

wherein

-   R¹, optionally mono- or di-substituted with R^(s), is selected from    the group consisting of —H, —C₁₋₇alkyl, —C₂₋₇alkenyl, —C₂₋₇alkynyl,    and —C₃₋₇cycloalkyl;    -   R^(s) is independently selected from the group consisting of        —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₃₋₆cycloalkyl, phenyl, pyridyl,        furanyl, thienyl, benzyl, pyrimidinyl, pyrrolyl, halo, —OH,        —OC₁₋₆alkyl, —OC₃₋₆cycloalkyl, -Ophenyl, -Obenzyl, —SH,        —SC₁₋₆alkyl, —SC₃₋₆cycloalkyl, -Sphenyl, -Sbenzyl, —CN, —NO₂,        —N(R^(m))R^(n) (wherein R^(m) and R^(n) are independently H or        C₁₋₄alkyl), —(C═O)N(R^(m))R^(n), —(C═O)C₁₋₄alkyl, —SCF₃, —OCF₃,        —CF₃, —COOC₁₋₄alkyl, and —COOH;-   n is 1 or 2;-   X is O or S;-   in the A-containing ring, one of A is selected from the group    consisting of —O—, —S—, —NH, or —NC₁₋₄alkyl; one of A is ═CH—; and    one of A is ═CH— or ═N—; provided that only one A can contain a N,    and provided that the two adjacent A's are not simultaneously    heteroatoms;-   L is —C₁₋₄alkylene-;-   R², optionally mono- or di-substituted with R^(q), is independently    selected from the group consisting of —H, —C₁₋₇alkyl, —C₂₋₇alkenyl,    —C₂₋₇alkynyl, —C₃₋₇cycloalkyl, phenyl, benzyl, pyridinyl,    pyrimidinyl, furanyl, thienyl, pyrrolyl, and a 5-, 6-, or 7-membered    monocyclic non-aromatic heterocyclic ring having 1 or 2 heteroatom    members selected from O, S, —N═, >NH, and >NC₁₋₄alkyl, having 0, 1,    or 2 double bonds; and-   R³, optionally mono- or di-substituted with R^(q), is independently    selected from the group consisting of —C₁₋₇alkyl, —C₂₋₇alkenyl,    —C₂₋₇alkynyl, —C₃₋₇cycloalkyl, phenyl, benzyl, pyridinyl,    pyrimidinyl, furanyl, thienyl, pyrrolyl, and a 5-, 6-, or 7-membered    monocyclic non-aromatic heterocyclic ring having 1 or 2 heteroatom    members selected from O, S, —N═, >NH, and >NC₁₋₄alkyl, having 0, 1,    or 2 double bonds;    -   R^(q) is independently selected from the group consisting of        —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₃₋₆cycloalkyl, phenyl, pyridyl,        furanyl, thienyl, benzyl, pyrimidinyl, pyrrolyl, halo, —OH,        —OC₁₋₆alkyl, —OC₃₋₆cycloalkyl, -Ophenyl, -Obenzyl, —SH,        —SC₁₋₆alkyl, —SC₃₋₆cycloalkyl, -Sphenyl, -Sbenzyl, —CN, —NO₂,        —N(R^(y))R^(z) (wherein R^(y) and R^(z) are independently        selected from H and C₁₋₄alkyl; or R^(y) and R^(z) may be taken        together with the nitrogen of attachment to form a 5-, 6-, or        7-membered monocyclic heterocyclic ring having 1 or 2 additional        heteroatom members selected from O, S, —N═, >NH, and        >NC₁₋₄alkyl, said ring optionally substituted with halo or        —C₁₋₄alkyl), —(C═O)N(R^(y))R^(z), —(C═O)C₁₋₄alkyl, —SCF₃, —OCF₃,        —CF₃, and —COOC₁₋₄alkyl, and —COOH;-   or, alternatively-   R² and R³ may be taken together with the nitrogen of attachment to    form a ring, said ring selected from the group consisting of:    -   i) a 4-7 membered non-aromatic heterocyclic ring said        heterocyclic ring having 0 or 1 additional heteroatom members        separated from the nitrogen of attachment by at least one carbon        member and selected from O, S, —N═, >NH, and >NR^(pp), having 0,        1, or 2 double bonds, having 0, 1, or 2 carbon members which is        a carbonyl, having 0, 1, or 2 substituents R^(p); and    -   ii) a benzo or pyrido fused 4-7 membered non-aromatic        heterocyclic ring said heterocyclic ring having 0 or 1        additional heteroatom members separated from the nitrogen of        attachment by at least one carbon member and selected from O, S,        —N═, >NH, and >NR^(pp), having 0 or 1 additional double bonds,        having 0, 1, or 2 carbon members which is a carbonyl, and having        0, 1, or 2 substituents R^(p);    -   R^(p) is independently selected from the group consisting of        —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₃₋₆cycloalkyl, phenyl, pyridyl,        furanyl, thienyl, benzyl, pyrimidinyl, pyrrolyl, halo, —OH,        —OC₁₋₆alkyl, —OC₃₋₆cycloalkyl, -Ophenyl, -Obenzyl, —SH,        —SC₁₋₆alkyl, —SC₃₋₆cycloalkyl, -Sphenyl, -Sbenzyl, —CN, —NO₂,        —N(R^(y))R^(z) (wherein R^(y) and R^(z) are independently        selected from H and C₁₋₄alkyl; or R^(y) and R^(z) may be taken        together with the nitrogen of attachment to form a 5-, 6-, or        7-membered monocyclic heterocyclic ring having 1 or 2 additional        heteroatom members selected from O, S, —N═, >NH, and        >NC₁₋₄alkyl, said ring optionally substituted with halo or        —C₁₋₄alkyl), —(C═O)N(R^(y))R^(z), —(C═O)C₁₋₄alkyl, —SCF₃, —OCF₃,        —CF₃, —COOC₁₋₄alkyl, and —COOH;    -   R^(pp) is independently selected from the group consisting of        —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₃₋₆cycloalkyl, phenyl, pyridyl,        benzyl, pyrimidinyl, pyrrolyl, —(C═O)N(R^(y))R^(z),        —(C═O)C₁₋₄alkyl, —COOC₁₋₄alkyl, and —COOC₁₋₄benzyl;-   and enantiomers, diastereomers, hydrates, solvates and    pharmaceutically acceptable salts, esters and amides thereof.

Similarly, isomeric forms of the compounds of formula (I), and of theirpharmaceutically acceptable salts, esters, and amides, are encompassedwithin the present invention, and reference herein to one of suchisomeric forms is meant to refer to at least one of such isomeric forms.One of ordinary skill in the art will recognize that compounds accordingto this invention may exist, for example in a single isomeric formwhereas other compounds may exist in the form of a regioisomericmixture.

The invention also features pharmaceutical compositions containing suchcompounds and methods of using such compositions in the treatment orprevention of disease states mediated by histamine H₃ receptor activity.

The invention also features a pharmaceutical composition comprising acompound of the invention and a pharmaceutically acceptable carrier; andmethods of preparing or formulating such compositions. A composition ofthe invention may further include more than one compound of theinvention, or a combination therapy (combination formulation orcombination of differently formulated active agents).

The invention also provides methods of treating certain conditions anddiseases, each of which methods includes administering a therapeuticallyeffective (or jointly effective) amount of a compound or composition ofthe invention to a subject in need of such treatment. The disclosedcompounds are useful in methods for treating or preventing neurologicdisorders including sleep/wake and arousal/vigilance disorders (e.g.insomnia and jet lag), attention deficit hyperactivity disorders (ADHD),learning and memory disorders, cognitive dysfunction, migraine,neurogenic inflammation, dementia, mild cognitive impairment(pre-dementia), Alzheimer's disease, epilepsy, narcolepsy with orwithout associated cataplexy, cataplexy, disorders of sleep/wakehomeostasis, idiopathic somnolence, excessive daytime sleepiness (EDS),circadian rhythm disorders, sleep/fatigue disorders, fatigue, drowsinessassociated with sleep apnea, sleep impairment due to perimenopausalhormonal shifts, Parkinson's-related fatigue, MS-related fatigue,depression-related fatigue, chemotherapy-induced fatigue, eatingdisorders, obesity, motion sickness, vertigo, schizophrenia, substanceabuse, bipolar disorders, manic disorders and depression, as well asother histamine H₃ receptor mediated disorders such as upper airwayallergic response, asthma, itch, nasal congestion and allergic rhinitisin a subject in need thereof. For example, the invention featuresmethods for preventing, inhibiting the progression of, or treating upperairway allergic response, asthma, itch, nasal congestion and allergicrhinitis.

In yet another embodiment, the disclosed compounds may be used in acombination therapy method including administering a jointly effectivedose of an H₃ antagonist and administering a jointly effective dose of ahistamine H₁ antagonist, such as loratidine (CLARITIN™), desloratidine(CLARINEX™), fexofenadine (ALLEGRA™) and cetirizine (ZYRTEC™), for thetreatment of allergic rhinitis, nasal congestion, and allergiccongestion.

In yet another embodiment, the disclosed compounds may be used in acombination therapy method, including administering a jointly effectivedose of an H₃ antagonist and administering a jointly effective dose of aneurotransmitter re-uptake blocker, such as a selective serotoninre-uptake inhibitor (SSRI), a serotonin-norepinephrine reuptakeinhibitor, a noradrenergic reuptake inhibitor, or a non-selectiveserotonin, dopamine or norepinephrine re-uptake inhibitor, includingfluoxetine (PROZAC™), sertraline (ZOLOFT™), paroxetine (PAXIL™) andamitryptyline, for the treatment of depression, mood disorders orschizophrenia. In an alternative embodiment, the disclosed compounds maybe used in a combination therapy method, including administering ajointly effective dose of an H₃ antagonist and administering a jointlyeffective dose of modafinil, for example, for the treatment ofnarcolepsy, excessive daytime sleepiness (EDS), Alzheimer's disease,depression, attention deficit disorders, MS-related fatigue,post-anesthesia grogginess, cognitive impairment, schizophrenia,spasticity associated with cerebral palsy, age-related memory decline,idiopathic somnolence, or jet-lag.

Additional features and advantages of the invention will become apparentfrom the detailed description and examples below, and the appendedclaims.

DETAILED DESCRIPTION

-   Preferably, R¹ is selected from the group consisting of —H, methyl,    ethyl, propyl, isopropyl, butyl, isobutyl, propenyl, propargyl,    cyclopropyl, cyclobutyl, cyclopentyl, hydroxyethyl, methoxyethyl,    and diethylaminoethyl.-   More preferably, R¹ is selected from the group consisting of methyl,    ethyl, isopropyl, and cyclopropyl.-   Even more preferably, R¹ is isopropyl.-   Preferably, n is 1.-   Preferably, X is O.-   Preferably, the A-containing ring is selected from the group    consisting of furan, thiophene, pyrrole, oxazole, and thiazole.-   Preferably, A at the 4-position is O or S and the A's at the 1- and    2-positions are CH; A at the 2-position is S and the A's at the 1-    and 4-positions are CH; A at the 1-position is N(C₁₋₄alkyl) and the    A's at the 2- and 4-positions are CH; or A at the 2-position is S or    O, A at the 4-position is N and A at the 1-position is CH.-   More preferably, one of A is S or O.-   More preferably, the A-containing ring is furan or thiophene.-   Even more preferably, A at the 4-position is O.-   Even more preferably, A at the 4-position is S.-   Even more preferably, A at the 2-position is S.-   Preferably, L is methylene.-   Preferably, R² is independently selected from the group consisting    of —H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,    methoxyethyl, hydroxyethyl, piperidinylethyl, morpholinylethyl,    pyridylethyl, diethylaminoethyl, propenyl, propargyl, cyclopropyl,    cyclopentyl, cyclohexyl, phenyl, benzyl, pyridinyl, pyrrolyl,    pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, and    azepanyl.-   More preferably, R² is independently selected from the group    consisting of —H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,    methoxyethyl, cyclopropyl, piperidinylethyl, morpholinylethyl,    pyridylethyl, and diethylaminoethyl.-   Even more preferably, R² is independently selected from the group    consisting of —H, methyl, and methoxyethyl.-   Preferably, R³ is independently selected from the group consisting    of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxyethyl,    hydroxyethyl, piperidinylethyl, morpholinylethyl, pyridylethyl,    diethylaminoethyl, propenyl, propargyl, cyclopropyl, cyclopentyl,    cyclohexyl, phenyl, benzyl, pyridinyl, pyrrolyl, pyrrolidinyl,    piperidinyl, morpholinyl, thiomorpholinyl, and azepanyl.-   More preferably, R³ is independently selected from the group    consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl,    methoxyethyl, cyclopropyl, piperidinylethyl, morpholinylethyl,    pyridylethyl, and diethylaminoethyl.-   Even more preferably, R³ is independently selected from the group    consisting of methyl and methoxyethyl.-   Where R² and R³ are taken together with the nitrogen of attachment    to form a ring, preferably said ring is selected from the group    consisting of piperidine, morpholine, thiomorpholine, piperazine,    and pyrrolidine.-   More preferably, R² and R³ may be taken together with the nitrogen    of attachment to form a ring selected from the group consisting of    piperidine, morpholine, and piperazine.-   In an alternative embodiment, R² and R³ may be taken together with    the nitrogen of attachment to form 4-fluoropiperidine.-   Even more preferably, R² and R³ may be taken together with the    nitrogen of attachment to form a ring selected from the group    consisting of piperidine and morpholine.-   Preferably, R^(pp) is —C₁₋₆alkyl.

Any of the preferred substituents described above that can be optionallyfurther substituted with any of R^(s), R^(q), R^(p), or R^(pp) accordingto formula (I) are intended to be so optionally substituted.

It is understood that some compounds referred to herein are chiraland/or have geometric isomeric centers, for example E- and Z-isomers.The present invention encompasses all such optical isomers, includingstereoisomers and racemic mixtures, diastereomers, and geometric isomersthat possess the activity that characterizes the compounds of thisinvention. Compounds of the invention may exist as single enantiomers,mixtures of enantiomers, or racemic mixtures. In certain embodiments,the absolute configuration of a single enantiomer may be unknown. Inaddition, certain compounds referred to herein can exist in solvated aswell as unsolvated forms. It is understood that this inventionencompasses all such solvated and unsolvated forms that possess theactivity that characterizes the compounds of this invention.

Compounds according to the present invention that have been modified tobe detectable by some analytic technique are also within the scope ofthis invention. The compounds of the present invention may be labeledwith radioactive elements such as ¹²⁵I, ¹⁸F, ¹¹C, ⁶⁴Cu, and the like foruse in imaging or for radioactive treatment of patients. An example ofsuch compounds is an isotopically labeled compound, such as an ¹⁸Fisotopically labeled compound that may be used as a probe in detectionand/or imaging techniques, such as positron emission tomography (PET)and single-photon emission computed tomography (SPECT). Preferably,compounds of the present invention labeled with ¹⁸F or ¹¹C may be usedas a positron emission tomography (PET) molecular probe for studyingdisorders mediated by the histamine H₃ receptor and the serotonintransporter. Another example of such compounds is an isotopicallylabeled compound, such as a deuterium and/or tritium labeled compoundthat may be used in reaction kinetic studies. The compounds describedherein may be reacted with an appropriate functionalized radioactivereagents using conventional chemistry to provide radiolabeled compounds.

Pharmaceutically acceptable salts, esters, and amides includecarboxylate salts (e.g., C₁₋₈alkyl, C₃₋₈cycloalkyl, aryl,C₂₋₁₀heteroaryl, or C₂₋₁₀ non-aromatic heterocyclic), amino additionsalts, acid addition salts, esters, and amides that are within areasonable benefit/risk ratio, pharmacologically effective and suitablefor contact with the tissues of patients without undue toxicity,irritation, or allergic response. Representative salts for compounds offormula (I) displaying basic functionality include hydrobromide,hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate,oleate, palmitate, stearate, laurate, borate, benzoate, lactate,phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate,naphthylate, mesylate, glucoheptonate, lactiobionate, andlaurylsulfonate. Representative addition salts for compounds of formula(I) displaying acidic functionality are those that form non-toxic basesalts with such compounds. These salts may include alkali metal andalkali earth cations such as sodium, potassium, calcium, and magnesium,as well as non-toxic ammonium, quaternary ammonium, and amine cationssuch as tetramethyl ammonium, methylammonium, trimethylammonium, andethylammonium. See example, S. M. Berge, et al., “Pharmaceutical Salts,”J. Pharm. Sci., 1977, 66:1-19, which is incorporated herein byreference.

Representative pharmaceutically acceptable amides of the inventioninclude those derived from ammonia, primary C₁₋₆ alkyl amines andsecondary di(C₁₋₆alkyl) amines. Secondary amines include 5- or6-membered heterocyclic or heteroaromatic ring moieties containing atleast one nitrogen atom and optionally between 1 and 2 additionalheteroatoms. Preferred amides are derived from ammonia, C₁₋₃alkylprimary amines, and di(C₁₋₂alkyl)amines. Representative pharmaceuticallyacceptable esters of the invention include C₁₋₇alkyl, C₅₋₇cycloalkyl,phenyl, and phenyl(C₁₋₆)alkyl esters. Preferred esters include methylesters.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds that are readily convertible invivo into the required compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with the compoundspecifically disclosed or with a compound that may not be specificallydisclosed, but which converts to the specified compound in vivo afteradministration to the patient. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985. Inaddition to salts, the invention provides the esters, amides, and otherprotected or derivatized forms of the described compounds.

Preferred compounds of the present invention are selected from the groupconsisting of:

EX Compound Name 1(4-Isopropyl-piperazin-1-yl)-(5-piperidin-1-ylmethyl-furan-2-yl)-methanone; 2(4-Isopropyl-piperazin-1-yl)-(5-morpholin-4-ylmethyl-furan-2-yl)-methanone; 3(4-Isopropyl-piperazin-1-yl)-{5-[(2-methoxy-ethylamino)-methyl]-furan-2-yl}-methanone; 4(4-Isopropyl-piperazin-1-yl)-(5-piperidin-1-ylmethyl-thiophen-2-yl)-methanone; 5(4-Isopropyl-piperazin-1-yl)-(5-morpholin-4-ylmethyl-thiophen-2-yl)-methanone; 6(4-Isopropyl-piperazin-1-yl)-{5-[(2-methoxy-ethylamino)-methyl]-thiophen-2-yl}-methanone; 7(4-Isopropyl-piperazin-1-yl)-(5-piperidin-1-ylmethyl-thiophen-3-yl)-methanone; 8(4-Isopropyl-piperazin-1-yl)-(5-morpholin-4-ylmethyl-thiophen-3-yl)-methanone; 9(4-Isopropyl-piperazin-1-yl)-(1-methyl-4-piperidin-1-ylmethyl-1H-pyrrol-2-yl)-methanone; 10(4-Isopropyl-piperazin-1-yl)-(1-methyl-4-morpholin-4-ylmethyl-1H-pyrrol-2-yl)-methanone; 11(4-Isopropyl-piperazin-1-yl)-(2-piperidin-1-ylmethyl-thiazol-4-yl)-methanone; 12(4-Isopropyl-piperazin-1-yl)-(2-morpholin-4-ylmethyl-thiazol-4-yl)-methanone; 13(4-Isopropyl-piperazin-1-yl)-{2-[(2-methoxy-ethylamino)-methyl]-thiazol-4-yl}-methanone; 14(4-Isopropyl-piperazin-1-yl)-(2-piperidin-1-ylmethyl-oxazol-4-yl)-methanone; 15(4-Isopropyl-piperazin-1-yl)-(2-morpholin-4-ylmethyl-oxazol-4-yl)-methanone; 16(4-Isopropyl-piperazin-1-yl)-{2-[(2-methoxy-ethylamino)-methyl]-oxazol-4-yl}-methanone; 17(4-Isopropyl-piperazin-1-yl)-(5-piperidin-1-ylmethyl-furan-2-yl)-methanethione; 18[5-(4-Fluoro-piperidin-1-ylmethyl)-furan-2-yl]-(4-isopropyl-piperazin-1-yl)-methanone; and 19[5-(4-Fluoro-piperidin-1-ylmethyl)-furan-2-yl]-(4-isopropyl-piperazin-1-yl)-methanone, fumarate salt.

In a preferred embodiment, compounds of the present invention areselected from the group consisting of:

EX Compound Name 1(4-Isopropyl-piperazin-1-yl)-(5-piperidin-1-ylmethyl-furan-2-yl)-methanone; 4(4-Isopropyl-piperazin-1-yl)-(5-piperidin-1-ylmethyl-thiophen-2-yl)-methanone; 5(4-Isopropyl-piperazin-1-yl)-(5-morpholin-4-ylmethyl-thiophen-2-yl)-methanone; 6(4-Isopropyl-piperazin-1-yl)-{5-[(2-methoxy-ethylamino)-methyl]-thiophen-2-yl}-methanone; 7(4-Isopropyl-piperazin-1-yl)-(5-piperidin-1-ylmethyl-thiophen-3-yl)-methanone; 8(4-Isopropyl-piperazin-1-yl)-(5-morpholin-4-ylmethyl-thiophen-3-yl)-methanone; and 9(4-Isopropyl-piperazin-1-yl)-(1-methyl-4-piperidin-1-ylmethyl-1H-pyrrol-2-yl)-methanone.

The features and advantages of the invention are apparent to one ofordinary skill in the art. Based on this disclosure, including thesummary, detailed description, background, examples, and claims, one ofordinary skill in the art will be able to make modifications andadaptations to various conditions and usages. Publications describedherein are incorporated by reference in their entirety. Where chemicalsymbols are used, it is understood that they are read from left toright, and that otherwise their spatial orientation has no significance.

The compounds as described above may be made according to processeswithin the skill of the art and/or that are described in the schemes andexamples that follow. To obtain the various compounds herein, startingmaterials may be employed that carry the ultimately desired substituentsthough the reaction scheme with or without protection as appropriate.This may be achieved by means of conventional protecting groups, such asthose described in “Protective Groups in Organic Chemistry”, ed. J. F.W. McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts,“Protective Groups in Organic Synthesis”, 3^(rd) ed., John Wiley & Sons,1999. The protecting groups may be removed at a convenient subsequentstage using methods known from the art. Alternatively, it may benecessary to employ, in the place of the ultimately desired substituent,a suitable group that may be carried through the reaction scheme andreplaced as appropriate with the desired substituent. Such compounds,precursors, or prodrugs are also within the scope of the invention.

The compounds as described above may be made according to Schemes A-Dbelow. Persons skilled in the art will recognize that certain compoundsare more advantageously produced by one scheme as compared to the other.

Compounds of formula (I) can be prepared as shown in Scheme A, with thefollowing notes and additions. Commercially available esters (III) canbe hydrolyzed under standard conditions (such as aqueous LiOH indioxane) to form carboxylic acids of formula (IV). Alternatively, someacids of formula (IV) may also be obtained from commercial sources. Insitu formation of acid chlorides of formula (V) can be accomplishedusing Vilsmeier reagent or thionyl chloride, with or without a suitablesolvent such as dichloromethane. The acid chloride is converted to thecorresponding amides (VI) by treatment with a nucleophilic piperazine orazepine derivative in the presence of an acid scavenger such as TEA. Theamides can also be formed directly from acids (IV) using amide-couplingmethods known to those skilled in the art. The aldehyde functionalitycan then be reacted under conditions of reductive amination to providecompounds of formula (I). The aldehyde can be treated with a suitableprimary or secondary amine, with or without the addition of anactivating agent such as a protic or Lewis acid, and with an appropriatereducing agent such as sodium triacetoxyborohydride. The aldehyde mayalternatively be reduced to an alcohol, converted to a leaving groupsuch as a mesylate or chloride and displaced with an appropriate amineas shown below in Scheme B. The chloride could also be displaced withcyanide anion, and the resulting nitrile reduced to homologate thelinker by one additional carbon. Alternatively, the aldehyde may bereacted using Horner-Emmons chemistry followed by hydrogenation of thedouble bond to introduce an alkyl chain containing an additional twocarbons. The carboxamide may be converted to its corresponding thioamideby treatment with P₂S₅ or Lawesson's reagent.

Referring to Scheme B, there are the following notes and additions.Protected hydroxy acid (VII) can be prepared as described in byMacdonald, S. J. F., et al. (J. Med. Chem. 2002, 45(18):3878-3890).Alternative protecting groups can be employed to protect the alcoholfunctionality. Amides of formula (VIII) are formed using standardpeptide coupling conditions such as EDCl and HOBt, in a solvent such asdichloromethane. The amine coupling partner is an appropriatelysubstituted piperazine or azepine compound. Removal of the protectinggroup will form alcohols of formula (IX). In the case of a tert-butylester, a mild base such as K₂CO₃, in a protic solvent such as methanol,may be employed. If other protecting groups are used, appropriatedeprotection conditions will be known to one skilled in the art. Thefree alcohol is converted to a leaving group, such as a tosylate,mesylate, or chloride, using the appropriate sulfonyl chloride and aproton scavenger such as TEA, or thionyl or oxalyl chloride, at reducedtemperature. Compounds of formula (I) are generated from thedisplacement of the leaving group with the desired primary or secondaryamine in the presence of a suitable base such as K₂CO₃ or TEA.

Referring to Scheme C, there are the following notes and additions.Chloromethyl oxazole (XI) is prepared in a manner analogous to thatdescribed by Cardwell, K. S., et al. (Tetrahedron Lett. 2000,41(21):4239-4242). Displacement of the chloride is accomplished with asuitable primary or secondary amine, in a solvent such as acetonitrile,with or without heating to form esters of formula (XII). The esterfunctionality is then hydrolyzed under standard conditions such as LiOHin aqueous dioxane to produce the corresponding acid, which issubsequently converted into compounds of formula (I) using a piperazineor azepine derivative and standard peptide coupling conditions such asEDCl and HOBt with or without the addition of a tertiary amine base.

Compounds prepared according to the schemes described above may beobtained as single enantiomers, mixtures of enantiomers, or racemicmixtures. Where racemic (1:1) and non-racemic (not 1:1) mixtures ofenantiomers are obtained, single enantiomers may be isolated usingconventional separation methods known to one skilled in the art.Particularly useful separation methods may include chiralchromatography, recrystallization, resolution, diastereomeric saltformation, or derivatization into diastereomeric adducts followed byseparation.

The compounds of the present invention are modulators of the histamineH₃ receptor, and as such, the compounds are useful in the treatment ofhistamine H₃-mediated disease states.

Compounds of the present invention may be administered in pharmaceuticalcompositions to treat patients (humans and other mammals) with disordersmediated by the H₃ receptor. The disclosed compounds, alone or incombination (with, for example, a histamine H₁ receptor antagonist), areuseful for treating or preventing neurologic disorders includingsleep/wake and arousal/vigilance disorders (e.g. insomnia and jet lag),attention deficit hyperactivity disorders (ADHD), learning and memorydisorders, cognitive dysfunction, migraine, neurogenic inflammation,dementia, mild cognitive impairment (pre-dementia), Alzheimer's disease,epilepsy, narcolepsy with or without associated cataplexy, cataplexy,disorders of sleep/wake homeostasis, idiopathic somnolence, excessivedaytime sleepiness (EDS), circadian rhythm disorders, sleep/fatiguedisorders, fatigue, drowsiness associated with sleep apnea, sleepimpairment due to perimenopausal hormonal shifts, Parkinson's-relatedfatigue, MS-related fatigue, depression-related fatigue,chemotherapy-induced fatigue, eating disorders, obesity, motionsickness, vertigo, schizophrenia, substance abuse, bipolar disorders,manic disorders and depression, as well as other histamine H₃ receptormediated disorders such as upper airway allergic response, asthma, itch,nasal congestion and allergic rhinitis in a subject in need thereof.Excessive daytime sleepiness (EDS) may occur with or without associatedsleep apnea, shift work, fibromyalgia, MS, and the like.

The present invention also provides pharmaceutical compositionscomprising one or more compounds of this invention in association with apharmaceutically acceptable carrier and optionally additionalpharmaceutical agents such as H₁ antagonists, SSRIs, or modafinil. Thepharmaceutical compositions can be prepared using conventionalpharmaceutical excipients and compounding techniques known to thoseskilled in the art of preparing dosage forms. It is anticipated that thecompounds of the invention can be administered by oral, parenteral,rectal, topical, or ocular routes, or by inhalation. Preparations mayalso be designed to give slow release of the active ingredient. Thepreparation may be in the form of tablets, capsules, sachets, vials,powders, granules, lozenges, powders for reconstitution, liquidpreparations, or suppositories. Preferably, compounds may beadministered by intravenous infusion or topical administration, but morepreferably by oral administration.

For oral administration, the compounds of the invention can be providedin the form of tablets or capsules, or as a solution, emulsion, orsuspension. Tablets for oral use may include the active ingredient mixedwith pharmaceutically acceptable excipients such as inert diluents,disintegrating agents, binding agents, lubricating agents, sweeteningagents, flavoring agents, coloring agents and preservatives agents.Suitable inert fillers include sodium and calcium carbonate, sodium andcalcium phosphate, lactose, starch, sugar, glucose, methyl cellulose,magnesium stearate, mannitol, sorbitol, and the like; typical liquidoral excipients include ethanol, glycerol, water and the like. Starch,polyvinyl-pyrrolidone, sodium starch glycolate, microcrystallinecellulose, and alginic acid are suitable disintegrating agents. Bindingagents may include starch and gelatin. The lubricating agent, ifpresent, will generally be magnesium stearate, stearic acid or talc. Ifdesired, the tablets may be coated with a material such as glycerylmonostearate or glyceryl distearate to delay absorption in thegastrointestinal tract, or may be coated with an enteric coating.Capsules for oral use include hard gelatin capsules in which the activeingredient is mixed with a solid, semi-solid, or liquid diluent, andsoft gelatin capsules wherein the active ingredient is mixed with water,an oil such as peanut oil or olive oil, liquid paraffin, a mixture ofmono and di-glycerides of short chain fatty acids, polyethylene glycol400, or propylene glycol.

Liquids for oral administration may be suspensions, solutions, emulsionsor syrups or may be presented as a dry product for reconstitution withwater or other suitable vehicles before use. Compositions of such liquidmay contain pharmaceutically-acceptable excipients such as suspendingagents (for example, sorbitol, methyl cellulose, sodium alginate,gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminiumstearate gel and the like); non-aqueous vehicles, which include oils(for example, almond oil or fractionated coconut oil), propylene glycol,ethyl alcohol or water; preservatives (for example, methyl or propylp-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and,if needed, flavoring or coloring agents.

The compounds of this invention may also be administered by non-oralroutes. The compositions may be formulated for rectal administration asa suppository. For parenteral use, including intravenous, intramuscular,intraperitoneal, or subcutaneous routes, the compounds of the inventionwill generally be provided in sterile aqueous solutions or suspensions,buffered to an appropriate pH and isotonicity or in parenterallyacceptable oil. Suitable aqueous vehicles include Ringer's solution andisotonic sodium chloride. Such forms will be presented in unit dose formsuch as ampules or disposable injection devices, in multi-dose formssuch as vials from which the appropriate dose may be withdrawn, or in asolid form or pre-concentrate that can be used to prepare an injectableformulation. Another mode of administration of the compounds of theinvention may utilize a patch formulation to affect transdermaldelivery. The compounds of this invention may also be administered byinhalation, via the nasal or oral routes using a spray formulationconsisting of the compound of the invention and a suitable carrier.

Effective doses of the compounds of the present invention may beascertained by conventional methods. The specific dosage level requiredfor any particular patient will depend on a number of factors, includingseverity of the condition being treated, the route of administration,and the weight of the patient. In general, however, it is anticipatedthat the daily dose (whether administered as a single dose or as divideddoses) will be in the range 0.01 to 1000 mg per day, more usually from 1to 500 mg per day, and most usually from 10 to 200 mg per day. Expressedas dosage per unit body weight, a typical dose will be expected to bebetween 0.0001 mg/kg and 15 mg/kg, especially between 0.01 mg/kg and 7mg/kg, and most especially between 0.15 mg/kg and 2.5 mg/kg.

Preferably, oral doses range from about 0.05 to 200 mg/kg, daily, takenin 1 to 4 separate doses. Some compounds of the invention may be orallydosed in the range of about 0.05 to about 50 mg/kg daily, others may bedosed at 0.05 to about 20 mg/kg daily, while still others may be dosedat 0.1 to about 10 mg/kg daily. Infusion doses can range from about 1 to1000 μg/kg/min of inhibitor, admixed with a pharmaceutical carrier overa period ranging from several minutes to several days. For topicaladministration compounds of the present invention may be mixed with apharmaceutical carrier at a concentration of about 0.1% to about 10% ofdrug to vehicle.

The disclosed compounds are useful in combination with other therapeuticagents, including H₁ receptor antagonists, H₂ receptor antagonists, andneurotransmitter modulators such as SSRIs, serotonin-norepinephrinereuptake inhibitors, noradrenergic reuptake inhibitors, non-selectiveserotonin re-uptake inhibitors (NSSRIs), or other neuroactive agentssuch as modafinil.

Methods are known in the art for determining effective doses fortherapeutic and prophylactic purposes for the disclosed pharmaceuticalcompositions or the disclosed drug combinations, whether or notformulated in the same composition. For therapeutic purposes, the term“jointly effective amount” as used herein, means that amount of eachactive compound or pharmaceutical agent, alone or in combination, thatelicits the biological or medicinal response in a tissue system, animalor human that is being sought by a researcher, veterinarian, medicaldoctor or other clinician, which includes alleviation of the symptoms ofthe disease or disorder being treated. For prophylactic purposes (i.e.,inhibiting the onset or progression of a disorder), the term “jointlyeffective amount” refers to that amount of each active compound orpharmaceutical agent, alone or in combination, that inhibits in asubject the onset or progression of a disorder as being sought by aresearcher, veterinarian, medical doctor or other clinician, thedelaying of which disorder is mediated, at least in part, by themodulation of one or more histamine receptors. Thus, the presentinvention provides combinations of two or more drugs wherein, forexample, (a) each drug is administered in an independentlytherapeutically or prophylactically effective amount; (b) at least onedrug in the combination is administered in an amount that issub-therapeutic or sub-prophylactic if administered alone, but istherapeutic or prophylactic when administered in combination with thesecond or additional drugs according to the invention; or (c) both drugsare administered in an amount that is sub-therapeutic orsub-prophylactic if administered alone, but are therapeutic orprophylactic when administered together. Combinations of three or moredrugs are analogously possible. Methods of combination therapy includeco-administration of a single formulation containing all active agents;essentially contemporaneous administration of more than one formulation;and administration of two or more active agents separately formulated.

EXAMPLES

In order to illustrate the invention, the following examples areincluded. These examples do not limit the invention. They are only meantto suggest a method of practicing the invention. Those skilled in theart may find other methods of practicing the invention, which areobvious to them. However, those methods are deemed to be within thescope of this invention.

Protocol for Preparative Reversed-Phase HPLC

Gilson® instrument

Column: YMC-Pack ODS-A, 5 μm, 75×30 mm

Flow rate: 10 mL/min

Detection: λ=220 & 254 nm

Gradient (acetonitrile/water, 0.05% trifluoroacetic acid)

1)  0.0 min 20% acetonitrile/80% water 2) 20.0 min 99% acetonitrile/1%water

Protocol for HPLC (Reversed-Phase) Hewlett Packard Series 1100 Column:Agilent ZORBAX® C8, 5 μm, 4.6×150 mm

Flow rate: 1 mL/min

Detection: λ=220 & 254 nm

Gradient (acetonitrile/water, 0.05% trifluoroacetic acid)

1) 0.0 min 1% acetonitrile/99% water 2) 8.0 min 99% acetonitrile/1%water

Mass spectra were obtained on an Agilent series 1100 MSD using ESIionization (ESI) in either positive or negative modes as indicated.

NMR spectra were obtained on either a Bruker model DPX400 (400 MHz) orDPX500 (500 MHz) spectrometer. The format of the ¹H NMR data below is:chemical shift in ppm down field of the tetramethylsilane reference(multiplicity, coupling constant J in Hz, integration).

Example 1

(4-Isopropyl-piperazin-1-yl)-(5-piperidin-1-ylmethyl-furan-2-yl)-methanone

Step A. 5-(4-Isopropyl-piperazine-1-carbonyl)-furan-2-carbaldehyde.Vilsmeier reagent [(chloromethylene)dimethylammonium chloride, 0.820 g,6.43 mmol] was suspended in DCM (30 mL) under nitrogen with stirring andcooled to 0° C. To this suspension was added 5-formyl-2-furancarboxylicacid (0.900 g, 6.43 mmol) and the combined mixture was stirred at 0° C.for 30 min. The mixture was warmed to rt, stirred for another 1.5 h, andfiltered. The filtrate (containing 5-formyl-furan-2-carbonyl chloride)was set aside and maintained at 0° C. In a second flask,1-isopropyl-piperizine dihydrochloride (1.28 g, 6.37 mmol) in DCM (15mL) was cooled to 0° C. The solution was treated with TEA (2.250 g,22.30 mmol) slowly and then was warmed to rt and stirred for 30 min. Thereaction mixture was filtered and the filtrate was cooled to 0° C. Thissecond filtrate was then treated dropwise with the previously preparedsolution of 5-formyl-furan-2-carbonyl chloride at 0° C. The combinedmixture was stirred at 0° C. for 30 min and then at rt for 1 h. Thereaction mixture was cooled to 0° C. and filtered, and the filtrate waswashed with H₂O (2×15 mL), 0.5 N NaOH (1×15 mL), and satd. aq. NaCl(1×15 mL). The organic layer was separated, dried over anhydrous Na₂SO₄,filtered, and concentrated to yield the desired product (1.40 g, 87%).

Step B.(4-Isopropyl-piperazin-1-yl)-(5-piperidin-1-ylmethyl-furan-2-yl)-methanone.A mixture of 5-(4-isopropyl-piperazine-1-carbonyl)-furan-2-carbaldehyde(0.15 g, 0.60 mmole), piperidine (0.058 mL, 0.59 mmol) and NaB(OAc)₃H(0.19 g, 0.90 mmol) was stirred under nitrogen in DCM (6 mL) overnight.The reaction mixture was quenched with 1 M NaOH and stirred at rt for 30min. The mixture was diluted with H₂O and extracted with DCM (3×20 mL).The combined organic extracts were washed with H₂O, dried over anhydrousNa₂SO₄, filtered, and concentrated (0.18 g, 95%). The crude material waspurified on silica gel column using 0-5% 2 M NH₃ in MeOH/DCM to yieldthe title compound (0.095 g, 50%). MS (ESI): exact mass calcd. forC₁₈H₂₉N₃O₂, 319.23; m/z found, 320.5 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):7.13 (d, J=3.6, 1H), 6.81 (d, J=3.6, 1H), 3.76-3.71 (m, 4H), 3.65 (s,2H), 2.74-2.68 (m, 1H), 2.56-2.50 (m, 4H), 2.45-2.36 (br s, 4H),1.60-1.53 (m, 4H), 1.44-1.37 (m, 2H), 1.04 (d, J=6.6, 6H).

Example 2

(4-Isopropyl-piperazin-1-yl)-(5-morpholin-4-ylmethyl-furan-2-yl)-methanone

The title compound was prepared in a manner similar to that described inExample 1, Step B. MS (ESI): exact mass calcd. for C₁₇H₂₇N₃O₃, 321.21;m/z found, 322.5 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 6.89 (d, J=3.3, 1H),6.30 (d, J=3.3, 1H), 3.90-3.76 (br m, 4H), 3.7 (t, J=4.6, 4H), 3.58 (s,2H), 2.82-2.72 (br s, 1H), 2.65-2.55 (br s, 4H), 2.50-2.46 (m, 4H), 1.05(d, J=6.3, 6H).

Example 3

(4-Isopropyl-piperazin-1-yl)-{5-[(2-methoxy-ethylamino)-methyl]-furan-2-yl}-methanone

The title compound was prepared in a manner similar to that described inExample 1, Step B. MS (ESI): exact mass calcd. for C₁₆H₂₇N₃O₃, 309.21;m/z found, 310.5 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 6.84-6.79 (m, 1H),6.25-6.20 (m, 1H), 3.83-3.66 (m, 6H), 3.49-3.24 (m, 5H), 2.79-2.60 (m,2H), 2.55-2.45 (m, 4H), 2.37-2.20 (m, 2H), 1.00 (d, J=6.6, 6H).

Example 4

(4-Isopropyl-piperazin-1-yl)-(5-piperidin-1-ylmethyl-thiophen-2-yl)-methanone

Step A. 5-(4-Isopropyl-piperazine-1-carbonyl)-thiophene-2-carbaldehyde.The title compound was prepared in a manner similar to that described inExample 1, Step A.

Step B.(4-Isopropyl-piperazin-1-yl)-(5-piperidin-1-ylmethyl-thiophen-2-yl)-methanone.The title compound was prepared in a manner similar to that described inExample 1, Step B. MS (ESI): exact mass calcd. for C₁₈H₂₉N₃OS, 335.20;m/z found, 336.5 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 6.87 (d, J=3.3, 1H),6.25 (d, J=3.3, 1H), 3.83-3.71 (br s, 4H), 3.54 (br s, 2H), 2.74-2.67(m, 1H), 2.60-2.50 (m, 4H), 2.47-2.37 (m, 4H), 1.63-1.50 (m, 4H),1.43-1.35 (m, 2H), 1.06 (d, J=6.6, 6H).

Example 5

(4-Isopropyl-piperazin-1-yl)-(5-morpholin-4-ylmethyl-thiophen-2-yl)-methanone

The title compound was prepared in a manner similar to that described inExample 1, Step B. MS (ESI): exact mass calcd. for C₁₇H₂₇N₃O₂S, 337.18;m/z found, 338.5 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.13 (d, J=3.6, 1H),6.83 (d, J=3.6, 1H), 3.78-3.73 (m, 4H), 3.70 (t, J=4.9, 4H), 3.68-3.65(m, 2H), 2.78-2.70 (m, 1H), 2.58-2.53 (m, 4H), 2.51-2.45 (m, 4H), 1.05(d, J=6.6, 6H).

Example 6

(4-Isopropyl-piperazin-1-yl)-{5-[(2-methoxy-ethylamino)-methyl]-thiophen-2-yl}-methanone

The title compound was prepared in a manner similar to that described inExample 1, Step B. MS (ESI): exact mass calcd. for C₁₆H₂₇N₃O₂S, 325.18;m/z found, 326.4 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.15 (d, J=3.6, 1H),6.86 (d, J=3.6, 1H), 4.00 (s, 2H), 3.81-3.73 (m, 4H), 3.52-3.48 (m, 2H),3.35 (s, 3H), 2.82 (t, J=5.2, 2H), 2.80-2.70 (m, 1H), 2.60-2.52 (m, 4H).

Example 7

(4-Isopropyl-piperazin-1-yl)-(5-piperidin-1-ylmethyl-thiophen-3-yl)-methanone

Step A. 4-(4-Isopropyl-piperazine-1-carbonyl)-thiophene-2-carbaldehyde.The title compound was prepared in a manner similar to that described inExample 1, Step A.

Step B.(4-Isopropyl-piperazin-1-yl)-(5-piperidin-1-ylmethyl-thiophen-3-yl)-methanone.The title compound was prepared in a manner similar to that described inExample 1, Step B, with the addition of acetic acid (1 eq.) to thereaction. MS (ESI): exact mass calcd. for C₁₈H₂₉N₃OS, 335.20; m/z found,336.4 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.40-7.36 (m, 1H), 7.00-6.96 (m,1H), 3.70-3.65 (br s, 2H), 2.78-2.70 (m, 1H), 2.60-2.39 (m, 8H),1.65-1.55 (m, 8H), 1.47-1.39 (m, 2H), 1.06 (d, J=6.6, 6H).

Example 8

(4-Isopropyl-piperazin-1-yl)-(5-morpholin-4-ylmethyl-thiophen-3-yl)-methanone

The title compound was prepared in a manner similar to that described inExample 1, Step B, with the addition of acetic acid (1 eq.) to thereaction. MS (ESI): exact mass calcd. for C₁₇H₂₇N₃O₂S, 337.18; m/zfound, 338.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.38 (d, J=1.4, 1H),6.99-6.98 (m, 1H), 3.78-3.58 (m, 10H), 2.80-2.66 (m, 1H), 2.58-2.43 (m,8H), 1.05 (d, 6.3, 6H).

Example 9

(4-Isopropyl-piperazin-1-yl)-(1-methyl-4-piperidin-1-ylmethyl-1H-pyrrol-2-yl)-methanone

Step A. 4-Formyl-1-methyl-1H-pyrrole-2-carboxylic acid.Methyl-4-formyl-1-methyl-1H-pyrrole-2-carboxylate (1.00 g, 5.98 mmol)was dissolved in dioxane (10 mL) and 1 M aq. LiOH (6 mL) was added atrt. After 18 h, the reaction mixture was concentrated to obtain thecrude acid as the lithium salt, which was carried forward to the nextstep.

Step B.5-(4-Isopropyl-piperazine-1-carbonyl)-1-methyl-1H-pyrrole-3-carbaldehyde.4-Formyl-1-methyl-1H-pyrrole-2-carboxylic acid, lithium salt, (1.08 g.)was diluted with thionyl chloride (20 mL) and heated at reflux undernitrogen for 1.5 h. The reaction mixture was carefully concentrated. Theresidue was co-evaporated with toluene (3×) to remove residual HCl, andthen was kept under vacuum for 2 h. Separately, a solution of1-isopropyl-piperazine dihydrochloride (1.21 g, 6.00 mmol) in DCM (50mL) was cooled to 0-5° C. TEA (2.23 mL, 24.0 mmol) was added slowly,followed by the above acid chloride solution in DCM (50 mL). Theresulting mixture was allowed to stir overnight at rt. The mixture wasconcentrated to yield the crude product (3.78 g), which was purified onsilica gel column using 2-6% 2 M NH₃ in MeOH/DCM to yield the titlecompound (0.20 g).

Step C.(4-Isopropyl-yl)-(1-methyl-4-piperidin-1-ylmethyl-1H-pyrrol-2-yl)-methanone.The title compound was prepared in a manner similar to that described inExample 1, Step B. MS (ESI): exact mass calcd. for C₁₉H₃₂N₄O, 332.26;m/z found, 333.5 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 6.58 (d, J=1.6, 1H),6.24 (d, J=1.6, 1H), 3.76-3.70 (m, 7H), 3.32 (s, 2H), 2.75-2.66 (m, 1H),2.53-2.50 (m, 4H), 2.41-2.27 (m, 4H), 1.59-1.51 (m, 4H), 1.43-1.35 (m,2H), 1.04 (d, J=6.6, 6H).

Example 10

(4-Isopropyl-piperazin-1-yl)-(1-methyl-4-morpholin-4-ylmethyl-1H-pyrrol-2-yl)-methanone

The title compound was prepared in a manner similar to that described inExample 9. MS (ESI): exact mass calcd. for C₁₈H₃₀N₄O₂, 334.24; m/zfound, 335.5 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 6.59 (d, J=1.6, 1H), 6.24(d, J=1.9, 1H), 3.75-3.70 (m, 7H), 3.68 (t, J=4.7, 4H), 3.33 (s, 2H),2.74-2.66 (m, 1H), 2.52 (t, J=4.9, 4H), 2.44-2.38 (m, 4H), 1.04 (d,J=6.6, 6H).

Example 11

(4-Isopropyl-piperazin-1-yl)-(2-piperidin-1-ylmethyl-thiazol-4-yl)-methanone

Step A. 2-(2,2-Dimethyl-propionyloxymethyl)-thiazole-4-carboxylic acid.A solution of 2-(tert-butylcarbonyloxy)thioacetamide (4.25 g, 24.2mmol), bromopyruvic acid (4.60 g., 27.5 mmol), and 4 Å activatedmolecular sieves (27.0 g) in EtOH (250 mL) was heated at reflux for 15h. The mixture was cooled to rt, filtered carefully, and washed withEtOH (3×50 mL). The filtrate and the washings were combined andconcentrated to yield a light yellow crude solid (6.42 g), which wascarried on to the next step without purification. MS (ESI): exact masscalcd. for C₁₀H₁₃NO₄S, 243.06; m/z found, 267.3 [M+Na]⁺.

Step B. 22-Dimethyl-propionic acid4-(4-isopropyl-piperazine-1-carbonyl)-thiazol-2-ylmethyl ester. Thecrude product from Step A (6.42 g, 24.2 mmol), 1-isopropyl-piperazinedihydrochloride (5.36 g., 26.68 mmol) and 1-hydroxybenzotriazole (4.915g., 36.38 mmol) were dissolved into a mixture of N-methylmorpholine(14.72 g., 101.20 mmol) and DCM (120 mL). The mixture was stirred for 30min under nitrogen. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (6.97 g, 36.4 mmol) was added, and the reaction mixturewas stirred for 18 h at rt. The reaction was quenched by the addition of1 M NaOH (25 mL), and was stirred for 1 h. The mixture was diluted withwater and extracted with DCM (3×60 mL). The combined organic extractswere washed with H₂O, dried over Na₂SO₄, filtered, and concentrated toyield dark brown crude oil (6.2 g). The crude product was purified onsilica gel column using 30-50% acetone-DCM to give the title compound asa brown oil (3.9 g, 46%). ¹H NMR (500 MHz, CDCl₃): 7.89 (s, 1H), 5.38(s, 2H), 3.90-3.84 (m, 2H), 3.81-3.75 (m, 2H), 2.75-2.69 (m, 1H),2.62-2.50 (m, 4H), 1.27-1.23 (s, 9H), 1.05 (d, J=6.3, 6H).

Step C.(2-Hydroxymethyl-thiazol-4-yl)-(4-isopropyl-piperazin-1-yl)-methanone. Amixture of 2,2-dimethyl-propionic acid4-(4-isopropyl-piperazine-1-carbonyl)-thiazol-2-ylmethyl ester (3.85 g,10.8 mmol), potassium carbonate (3.06 g., 21.7 mmol), MeOH (130 mL), andH₂O (50 mL) was heated at reflux for 12 h. The reaction mixture wascooled to rt and extracted with DCM (8×50 mL). The combined organicextracts were dried over Na₂SO₄ and concentrated to yield a yellowishsolid (2.14 g, 73.3%). MS (ESI): exact mass calcd. for C₁₂H₁₉N₃O₂S,269.12; m/z found, 270.4 [M+H]⁺.

Step D. Methanesulfonic acid4-(4-isopropyl-piperazine-1-carbonyl)-thiazol-2-ylmethyl ester.(2-Hydroxymethyl-thiazol-4-yl)-(4-isopropyl-piperazin-1-yl)-methanone(0.95 g. 3.5 mmol) and TEA (0.542 mL, 3.89 mmol) were suspended in DCM(50 mL). The suspension was cooled to 0° C. and methanesulfonyl chloride(0.3 mL) was added dropwise. The mixture was stirred at 0° C. for 30min, then warmed to rt and stirred for 2 h. The mixture was concentratedat rt to yield the title compound (0.50 g, 41%). The crude mesylate wascarried forward to the next step. MS (ESI): exact mass calcd. forC₁₄H₂₂N₂O₄S₂, 347.10; m/z found, 348.5 [M+H]⁺.

Step E.(4-Isopropyl-piperazin-1-yl)-(2-piperidin-1-ylmethyl-thiazol-4-yl)-methanone.A mixture of methanesulfonic acid4-(4-isopropyl-piperazine-1-carbonyl)-thiazol-2-ylmethyl ester (0.052 g,0.14 mmol), anhydrous potassium carbonate (0.054 g., 0.43 mmol), andpiperidine (0.016 mL, 0.16 mmol) in anhydrous acetonitrile (4 mL) wasstirred at rt for 18 h. The reaction mixture was diluted with H₂O andextracted with DCM (4×15 mL). The combined organic extracts were driedover Na₂SO₄, filtered, and concentrated to yield the crude product(0.045 g). The crude material was purified on silica gel column using0-5% 2 M NH₃ in MeOH/DCM to give the title compound (0.03 g, 62%). MS(ESI): exact mass calcd. for C₁₇H₂₈N₄OS, 336.20; m/z found, 337.5[M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.80 (s, 1H), 3.90-3.74 (m, 4H),2.77-2.67 (m, 1H), 2.63-2.47 (m, 8H), 1.73-1.57 (m, 6H), 1.50-1.41 (m,2H), 1.05 (d, J=6.6, 6H).

Example 12

(4-Isopropyl-piperazin-1-yl)-(2-morpholin-4-ylmethyl-thiazol-4-yl)-methanone

The title compound was prepared in a manner similar to that described inExample 11, Step E. MS (ESI): exact mass calcd. for C₁₆H₂₆N₄O₂S, 338.18;m/z found, 339.4 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.80 (s, 1H),3.84-3.80 (m, 4H), 3.78-3.74 (m, 4H), 3.72 (t, J=4.7, 4H), 2.72-2.66 (m,1H), 2.58 (t, J=4.7, 6H), 2.52-2.47 (m, 2H), 1.02 (d, J=6.6, 6H).

Example 13

(4-Isopropyl-piperazin-1-yl)-{2-[(2-methoxy-ethylamino)-methyl]-thiazol-4-yl}-methanone

The title compound was prepared in a manner similar to that described inExample 11, Step E. MS (ESI): exact mass calcd. for C₁₅H₂₆N₄O₂S, 326.18;m/z found, 327.4 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.78 (s, 1H), 4.12 (s,2H), 3.89-3.73 (m, 4H), 3.52-3.49 (m, 2H), 3.36 (s, 3H), 2.88-2.85 (m,2H), 2.74-2.68 (m, 1H), 2.62-2.45 (m, 4H), 1.04 (d, J=6.6, 6H).

Example 14

(4-Isopropyl-piperazin-1-yl)-(2-piperidin-1-ylmethyl-oxazol-4-yl)-methanone

Step A. 2-Chloromethyl-oxazole-4-carboxylic acid ethyl ester. Sodiummethoxide (25% w/w solution in MeOH, 0.07 mL, 0.30 mmol) was added to amixture of DCM (21.5 mL) and MeOH (2.40 mL) and the mixture was cooledto −5° C. Dichloroacetonitrile was added (3.25 g., 29.6 mmol) dropwiseover 45 min, maintaining the temperature below 0° C., and the mixturewas then stirred for 60 min at 0° C. Serine ethyl ester hydrochloride(5.00 g, 29.5 mmol) was added and the mixture was stirred overnight at20° C. The slurry was diluted with DCM and H₂O (12 mL), and wasextracted with DCM (20-25 mL). The combined organic extracts wereconcentrated at atmospheric pressure to 15 mL. N,N-Diisopropylethylamine(7.72 mL, 44.3 mmol) was added and the mixture was heated at 50° C. for5 h. The mixture was cooled to rt and was stirred overnight. The mixturewas diluted with DCM (19 mL) and cooled to 5° C. To this mixture wascautiously added 2 M HCl (21.6 mL). The organic layer was separated,washed with H₂O (12 mL), and concentrated to 27 mL. This solutioncontaining the title compound was carried forward for alkylation. Thesolution was divided into 3 equal parts and it was assumed that eachpart (9 mL) contained 9.80 mmol of the crude product.

Step B. 2-Piperidin-1-ylmethyl-oxazole-4-carboxylic acid ethyl ester. Asolution of 2-chloromethyl-oxazole-4-carboxylic acid ethyl ester(estimated 9.0 mL, 9.8 mmol) was cooled to 15° C. and piperidine (1.92mL, 19.4 mmol) was added slowly over 10 min. The mixture was heated atreflux for 30 min and then cooled to −5° C. and filtered. The filtratewas concentrated at rt under vacuum (40 mm Hg). The resulting oily crudeproduct (approximately 2.38 g) was carried on to the saponificationstep.

Step C. 2-Piperidin-1-ylmethyl-oxazole-4-carboxylic acid. To a rtsolution of the crude ester from Step B (est. 2.38 g) in dioxane (50 mL)was added 1 M aq. LiOH (11 mL). After 18 h, the reaction mixture wasconcentrated on a rotary evaporator at low temperature to yield thecrude acid as its lithium salt (1.73 g). The crude product was carriedto the next step. MS (ESI): exact mass calcd. for C₁₀H₁₄N₂O₃, 210.10;m/z found, 211.4 [M+H]⁺.

Step D.(4-Isopropyl-piperazin-1-yl)-(2-piperidin-1-ylmethyl-oxazol-4-yl)-methanone.A solution of 2-piperidin-1-ylmethyl-oxazole-4-carboxylic acid, lithiumsalt (0.400 g, 1.85 mmol), 1-isopropyl-piperazine dihydrochloride (0.409g., 2.03 mmol), 1-hydroxybenzotriazole (0.300 g., 2.22 mmol), andN-methylmorpholine (1.22 mL, 11.1 mmol) in anhydrous DCM (18 mL) wasstirred for 1 h. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (0.426 g., 2.22 mmol) was added, and the reaction mixturewas stirred at rt for 18 h. The reaction was quenched by the addition of1 M NaOH (20 mL) was stirred for 1 h. The resulting mixture wasextracted with DCM (3×30 mL). The combined organic extracts were washedwith H₂O, dried over Na₂SO₄, filtered, and concentrated to yield thecrude product (0.700 g). The crude product was purified on silica gelcolumn using 0-5% 2 M NH₃ in MeOH/DCM to provide the title compound(0.345 g, 58.2%). MS (ESI): exact mass calcd. for C₁₇H₂₈N₄O₂, 320.22;m/z found, 321.5 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 8.10 (s, 1H),4.09-4.00 (m, 2H), 3.77-3.70 (m, 2H), 3.68-3.65 (s, 2H), 2.75-2.67 (m,1H), 2.58-2.52 (m, 4H), 2.47 (t, J=4.7, 4H), 1.63-1.57 (m, 4H),1.45-1.39 (m, 2H), 1.04 (d, J=6.6, 6H).

Example 15

(4-Isopropyl-piperazin-1-yl)-(2-morpholin-4-ylmethyl-oxazol-4-yl)-methanone

Step A. 2-Morpholin-4-ylmethyl-oxazole-4-carboxylic acid ethyl ester.The title compound was prepared in a manner similar to that described inExample 14,

Step B. MS (ESI): exact mass calcd. for C₁₁H₁₆N₂O₄, 240.11; m/z found,241.4 [M+H]⁺.

Step B. 2-Morpholin-4-ylmethyl-oxazole-4-carboxylic acid. The titlecompound was prepared in a manner similar to that described in Example14, Step C.

Step C.(4-Isopropyl-piperazin-1-yl)-(2-morpholin-4-ylmethyl-oxazol-4-yl)-methanone.The title compound was prepared in a manner similar to that described inExample 14, Step D. MS (ESI): exact mass calcd. for C₁₆H₂₆N₄O₃, 322.20;m/z found, 323.5 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 8.13 (s, 1H),4.10-4.00 (m, 2H), 3.76-3.71 (m, 6H), 3.70 (s, 2H), 2.75-2.68 (m, 1H),2.60-2.52 (m, 8H), 1.05 (d, J=6.6, 6H).

Example 16

(4-Isopropyl-piperazin-1-yl)-{2-[(2-methoxy-ethylamino)-methyl]-oxazol-4-yl}-methanone

Step A. 2-[(2-Methoxy-ethylamino)-methyl]-oxazole-4-carboxylic acidethyl ester. The title compound was prepared in a manner similar to thatdescribed in Example 14, Step B.

Step B. 2-[(2-Methoxy-ethylamino)-methyl]-oxazole-4-carboxylic acid. Thetitle compound was prepared in a manner similar to that described inExample 14, Step C. MS (ESI): exact mass calcd. for C₈H₁₂N₂O₄, 200.08;m/z found, 201.3 [M+H]⁺.

Step C.2-{[tert-Butoxycarbonyl-(2-methoxy-ethyl)-amino]-methyl}-oxazole-4-carboxylicacid. To a solution of2-[(2-methoxy-ethylamino)-methyl]-oxazole-4-carboxylic acid, lithiumsalt (1.20 g, 5.82 mmol) in THF (30 mL) was addedN,N-diisopropylethylamine (2.02 mL, 11.6 mmol), followed by a solutionof di-tert-butyl dicarbonate (2.54 g, 11.6 mmol) in THF (15 mL). Thereaction mixture was stirred overnight at rt. The mixture was dilutedwith DCM (60 mL) and extracted with H₂O (50 mL). The aqueous phase wasconcentrated to yield the crude product (1.104 g).

Step D.[4-(4-Isopropyl-piperazine-1-carbonyl)-oxazol-2-ylmethyl]-(2-methoxy-ethyl)-carbamicacid tert-butyl ester. A mixture of the crude material from Step C (1.10g, 3.67 mmol), 1-isopropyl-piperazine dihydrochloride (0.810 g, 4.03mmol), 1-hydroxybenzotriazole (0.595 g, 4.40 mmol), andN-methylmorpholine (2.42 mL, 22.0 mmol) in DMF (20 mL) was stirred for 1h. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.845 g,4.40 mmol) was added and the mixture was stirred overnight. The reactionmixture was diluted with H₂O (500 mL) and extracted with DCM (3×60 mL).The combined organic extracts were washed with H₂O (3×300 mL), driedover Na₂SO₄, filtered and concentrated to yield the crude title compound(1.30 g). MS (ESI): exact mass calcd. for C₂₀H₃₄N₄O₅, 410.25; m/z found,411.5 [M+H]⁺.

Step E.(4-Isopropyl-piperazin-1-yl)-{2-[(2-methoxy-ethylamino)-methyl]-oxazol-4-yl}-methanone.To a solution of the crude product from Step D in anhydrous dioxane (25mL) was added 2 M HCl in dioxane (15 mL). The reaction mixture wasstirred overnight and then was concentrated under vacuum to yield thecrude product (0.240 g), which was purified on a silica gel column using0-5% 2 M NH₃ in MeOH/DCM to give the title compound (0.050 g, 6%). MS(ESI): exact mass calcd. for C₁₅H₂₆N₄O₃, 310.20; m/z found, 311.5[M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 8.08 (s, 1H), 4.10-4.01 (m, 2H), 3.94(s, 2H), 3.76-3.69 (m, 2H), 3.52-3.48 (m, 2H), 3.34 (s, 3H), 2.83-2.80(m, 2H), 2.74-2.67 (m, 1H), 2.58-2.51 (m, 4H), 1.04 (d, J=6.6, 6H).

Example 17

(4-Isopropyl-piperazin-1-yl)-(5-piperidin-1-ylmethyl-furan-2-yl)-methanethione

A solution of(4-isopropyl-piperazin-1-yl)-(5-piperidin-1-ylmethyl-furan-2-yl)-methanone(Example 1, 1 equiv.) and Lawesson's reagent (2.1 equiv.) in THF isheated at reflux (70° C.) for 48 h. The reaction is cooled to roomtemperature and the solvent is removed in vacuo. Chromatography of theresidue on a silica gel column using 1-6% 2 M NH₃ in MeOH/DCM) providesthe title compound.

Example 18

[5-(4-Fluoro-piperidin-1-ylmethyl)-furan-2-yl]-(4-isopropyl-piperazin-1-yl)-methanone

The title compound was prepared in a manner similar to that described inExample 1, Step B. ¹H NMR (500 MHz, CDCl₃): 6.88 (d, J=3.4, 1H), 6.28(d, J=3.4, 1H), 4.71-4.60 (m, 1H), 3.77 (br s, 4H), 3.59 (s, 2H),2.74-2.69 (m, 1H), 2.63-2.58 (m, 2H), 2.55 (t, J=5.0, 4H), 2.47-2.42 (m,2H), 1.94-1.84 (m, 4H), 1.04 (d, J=6.6, 6H).

Example 19

[5-(4-Fluoro-piperidin-1-ylmethyl)-furan-2-yl]-(4-isopropyl-piperazin-1-yl)-methanone,fumarate salt

To a solution of the amine (0.495 g, 1.48 mmol) in EtOH (5 mL) washeated with a warmed solution of fumaric acid (0.171 g, 1.0 eq.) in EtOH(4 mL). The resulting homogeneous solution was concentrated in vacuo toprovide 0.609 g (90%) of the fumarate salt. ¹H NMR (500 MHz, DMSO-d₆):6.89 (d, J=3.3, 1H), 6.41 (d, J=3.3, 1H), 4.71-4.59 (m, 1H), 3.63 (br s,4H), 3.54 (s, 2H), 3.41-3.35 (m, 2H), 2.74-2.71 (m, 1H), 2.49-2.44 (m,4H), 2.34-2.30 (m, 2H), 1.86-1.65 (m, 4H), 0.97 (d, J=6.6, 6H).

Biology Example A. Transfection of Cells with Human Histamine Receptor

Cells were grown to about 70% to 80% confluence and removed from theplate with trypsin and pelleted in a clinical centrifuge. The pellet wasthen re-suspended in 400 μL of complete media and transferred to anelectroporation cuvette with a 0.4 cm gap between the electrodes(Bio-Rad #165-2088). One μg supercoiled H₃ receptor cDNA was added tothe cells and mixed gently. The voltage for the electroporation was setat 0.25 kV and the capacitance was set at 960 μF. After electroporationthe cells were diluted with 10 mL of complete media and were plated ontofour 10 cm dishes at the following ratios: 1:20, 1:10, 1:5, and 1:2. Thecells were allowed to recover for 24 h before adding 600 μg G-418.Colonies that survived selection were grown and tested. SK-N-MC cellswere used because they give efficient coupling for inhibition ofadenylate cyclase. The clones that gave the most robust inhibition ofadenylate cyclase in response to histamine were used for further study.

B. [³H]-N-Methylhistamine Binding

Cell pellets from histamine H₃ receptor-expressing SK-N-MC cells werehomogenized in 50 mM Tris HCl/0.5 mM EDTA. Supernatants from an 800 gspin were collected and were recentrifuged at 30,000 g for 30 min.Pellets were re-homogenized in 50 mM Tris/5 mM EDTA (pH 7.4). Membraneswere incubated with 0.8 nM [³H]-N-methylhistamine plus/minus testcompounds for 60 min at 25° C. and were harvested by rapid filtrationover GF/C glass fiber filters (pretreated with 0.3% polyethylenimine)followed by four washes with buffer. Filters were added to 5 mL ofscintillation cocktail, and the signal was then counted on a liquidscintillation counter. Non-specific binding was defined with 10 μMhistamine. pK_(i) values were calculated based on a K_(D) of 0.8 nM anda ligand concentration ([L]) of 0.8 nM according to the formulaK_(i)=(IC₅₀)/(1+([L]/(KD)). Data are presented in Table 1.

TABLE 1 Biological Data. EX K_(i) (nM) 1 2 2 144 3 114 4 16 5 26 6 5 7 38 29 9 34 10 162 11 151 12 3000 13 2000 14 1000 15 3000 16 2000 19 64

1. A compound having histamine H₃ receptor modulating activity offormula (I):

wherein R¹, optionally mono- or di-substituted with R^(s), is selectedfrom the group consisting of —H, —C₁₋₇alkyl, —C₂₋₇alkenyl, —C₂₋₇alkynyl,and —C₃₋₇cycloalkyl; R^(s) is independently selected from the groupconsisting of —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₃₋₆cycloalkyl, phenyl,pyridyl, furanyl, thienyl, benzyl, pyrimidinyl, pyrrolyl, halo, —OH,—OC₁₋₆alkyl, —OC₃₋₆cycloalkyl, -Ophenyl, -Obenzyl, —SH, —SC₁₋₆alkyl,—SC₃₋₆cycloalkyl, -Sphenyl, -Sbenzyl, —CN, —NO₂, —N(R^(m))R^(n) (whereinR^(m) and R^(n) are independently H or C₁₋₄alkyl), —(C═O)N(R^(m))R^(n),—(C═O)C₁₋₄alkyl, —SCF₃, —OCF₃, —CF₃, —COOC₁₋₄alkyl, and —COOH; n is 1 or2; X is O or S; the A-containing ring is thiophene; L is —C₁₋₄alkylene-;R², optionally mono- or di-substituted with R^(q), is independentlyselected from the group consisting of —H, —C₁₋₇alkyl, —C₂₋₇alkenyl,—C₂₋₇alkynyl, —C₃₋₇cycloalkyl, phenyl, benzyl, pyridinyl, pyrimidinyl,furanyl, thienyl, pyrrolyl, and a 5-, 6-, or 7-membered monocyclicnon-aromatic heterocyclic ring having 1 or 2 heteroatom members selectedfrom O, S, —N═, >NH, and >NC₁₋₄alkyl, having 0, 1, or 2 double bonds;and R³, optionally mono- or di-substituted with R^(q) is independentlyselected from the group consisting of —C₁₋₁₇alkyl, —C₂₋₇alkenyl,—C₂₋₇alkynyl, —C₃₋₇cycloalkyl, phenyl, benzyl, pyridinyl, pyrimidinyl,furanyl, thienyl, pyrrolyl, and a 5-, 6-, or 7-membered monocyclicnon-aromatic heterocyclic ring having 1 or 2 heteroatom members selectedfrom O, S, —N═, >NH, and >NC₁₋₄alkyl, having 0, 1, or 2 double bonds;R^(q) is independently selected from the group consisting of —C₁₋₆alkyl,—C₂₋₆alkenyl, —C₃₋₆cycloalkyl, phenyl, pyridyl, furanyl, thienyl,benzyl, pyrimidinyl, pyrrolyl, halo, —OH, —OC₁₋₆alkyl, —OC₃₋₆cycloalkyl,-Ophenyl, -Obenzyl, —SH, —SC₁₋₆alkyl, —SC₃₋₆cycloalkyl, -Sphenyl,-Sbenzyl, —CN, —NO₂, —N(R^(y))R^(z) (wherein R^(y) and R^(z) areindependently selected from H and C₁₋₁₄alkyl; or R^(y) and R^(z) may betaken together with the nitrogen of attachment to form a 5-, 6-, or7-membered monocyclic heterocyclic ring having 1 or 2 additionalheteroatom members selected from O, S, —N═, >NH, and >NC₁₋₄alkyl, saidring optionally substituted with halo or —C₁₋₄alkyl),—(C═O)N(R^(y))R^(z), —(C═O)C₁₋₄alkyl, —SCF₃, —OCF₃, —CF₃, and—COOC₁₋₄alkyl, and —COOH; or, alternatively R² and R³ may be takentogether with the nitrogen of attachment to form a ring, said ringselected from the group consisting of: i) a 4-7 membered non-aromaticheterocyclic ring said heterocyclic ring having 0 or 1 additionalheteroatom members separated from the nitrogen of attachment by at leastone carbon member and selected from O, S, —N═, >NH, and >NR¹¹, having 0,1, or 2 double bonds, having 0, 1, or 2 carbon members which is acarbonyl, having 0, 1, or 2 substituents R^(p); and ii) a benzo orpyrido fused 4-7 membered non-aromatic heterocyclic ring saidheterocyclic ring having 0 or 1 additional heteroatom members separatedfrom the nitrogen of attachment by at least one carbon member andselected from O, S, —N═, >NH, and >NR^(pp), having 0 or 1 additionaldouble bonds, having 0, 1, or 2 carbon members which is a carbonyl, andhaving 0, 1, or 2 substituents R^(p); R^(p) is independently selectedfrom the group consisting of —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₃₋₆cycloalkyl,phenyl, pyridyl, furanyl, thienyl, benzyl, pyrimidinyl, pyrrolyl, halo,—OH, —OC₁₋₆alkyl, —OC₃₋₆cycloalkyl, -Ophenyl, -Obenzyl, —SH,—SC₁₋₆alkyl, —SC₃₋₆cycloalkyl, -Sphenyl, -Sbenzyl, —CN, —NO₂,—N(R^(y))R^(z) (wherein R^(y) and R^(z) are independently selected fromH and C₁₋₁₄alkyl; or R^(y) and R^(z) may be taken together with thenitrogen of attachment to form a 5-, 6-, or 7-membered monocyclicheterocyclic ring having 1 or 2 additional heteroatom members selectedfrom O, S, —N═, >NH, and >NC₁₋₄alkyl, said ring optionally substitutedwith halo or —C₁₋₄alkyl), —(C═O)N(R^(y))R^(z), —(C═O)C₁₋₄alkyl, —SCF₃,—OCF₃, —CF₃, —COOC₁₋₄alkyl, and —COOH; R^(pp) is independently selectedfrom the group consisting of —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₃₋₆cycloalkyl,phenyl, pyridyl, benzyl, pyrimidinyl, pyrrolyl, —(C═O)N(R^(y))R^(z),—(C═O)C₁₋₄alkyl, —COOC₁₋₄alkyl, and —COOC₁₋₄-benzyl; and enantiomers,diastereomers, hydrates, solvates and pharmaceutically acceptable salts,esters and amides thereof.
 2. The compound of claim 1 wherein R¹ isselected from the group consisting of —H, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, propenyl, propargyl, cyclopropyl,cyclobutyl, cyclopentyl, hydroxyethyl, methoxyethyl, anddiethylaminoethyl.
 3. The compound of claim 1 wherein R¹ is selectedfrom the group consisting of methyl, ethyl, isopropyl, and cyclopropyl.4. The compound of claim 1 wherein R¹ is isopropyl.
 5. The compound ofclaim 1 wherein n is
 1. 6. The compound of claim 1 wherein X is O. 7-13.(canceled)
 14. The compound of claim 1 wherein L is methylene.
 15. Thecompound of claim 1 wherein R² is independently selected from the groupconsisting of —H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,methoxyethyl, hydroxyethyl, piperidinylethyl, morpholinylethyl,pyridylethyl, diethylaminoethyl, propenyl, propargyl, cyclopropyl,cyclopentyl, cyclohexyl, phenyl, benzyl, pyridinyl, pyrrolyl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, and azepanyl.16. The compound of claim 1 wherein R² is independently selected fromthe group consisting of —H, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, methoxyethyl, cyclopropyl, piperidinylethyl, morpholinylethyl,pyridylethyl, and diethylaminoethyl.
 17. The compound of claim 1 whereinR² is independently selected from the group consisting of —H, methyl,and methoxyethyl.
 18. The compound of claim 1 wherein R³ isindependently selected from the group consisting of methyl, ethyl,propyl, isopropyl, butyl, isobutyl, methoxyethyl, hydroxyethyl,piperidinylethyl, morpholinylethyl, pyridylethyl, diethylaminoethyl,propenyl, propargyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl,benzyl, pyridinyl, pyrrolyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, and azepanyl.
 19. The compound of claim 1 wherein R³ isindependently selected from the group consisting of methyl, ethyl,propyl, isopropyl, butyl, isobutyl, methoxyethyl, cyclopropyl,piperidinylethyl, morpholinylethyl, pyridylethyl, and diethylaminoethyl.20. The compound of claim 1 wherein R³ is independently selected fromthe group consisting of methyl and methoxyethyl.
 21. The compound ofclaim 1 wherein R² and R³ may be taken together with the nitrogen ofattachment to form a ring selected from the group consisting ofpiperidine, morpholine, thiomorpholine, piperazine, and pyrrolidine. 22.The compound of claim 1 wherein R² and R³ may be taken together with thenitrogen of attachment to form a ring selected from the group consistingof piperidine, morpholine, and piperazine.
 23. The compound of claim 1wherein R² and R³ may be taken together with the nitrogen of attachmentto form 4-fluoropiperidine.
 24. The compound of claim 1 wherein R² andR³ may be taken together with the nitrogen of attachment to form a ringselected from the group consisting of piperidine and morpholine.
 25. Thecompound of claim 1 wherein R^(pp) is —C₁₋₆alkyl.
 26. A compoundselected from the group consisting of:(4-Isopropyl-piperazin-1-yl)-(5-piperidin-1-ylmethyl-thiophen-2-yl)-methanone;(4-Isopropyl-piperazin-1-yl)-(5-morpholin-4-ylmethyl-thiophen-2-yl)-methanone;(4-Isopropyl-piperazin-1-yl)-{5-[(2-methoxy-ethylamino)-methyl]-thiophen-2-yl}-methanone;(4-Isopropyl-piperazin-1-yl)-(5-piperidin-1-ylmethyl-thiophen-3-yl)-methanone;(4-Isopropyl-piperazin-1-yl)-(5-morpholin-4-ylmethyl-thiophen-3-yl)-methanone;27. A compound selected from the group consisting of:(4-Isopropyl-piperazin-1-yl)-(5-piperidin-1-ylmethyl-thiophen-2-yl)-methanone;(4-Isopropyl-piperazin-1-yl)-(5-morpholin-4-ylmethyl-thiophen-2-yl)-methanone;(4-Isopropyl-piperazin-1-yl)-{5-[(2-methoxy-ethylamino)-methyl]-thiophen-2-yl}-methanone;(4-Isopropyl-piperazin-1-yl)-(5-piperidin-1-ylmethyl-thiophen-3-yl)-methanone;(4-Isopropyl-piperazin-1-yl)-(5-morpholin-4-ylmethyl-thiophen-3-yl)-methanone;and.
 28. The compound of claim 1 wherein said pharmaceuticallyacceptable salt is an effective amino addition salt.
 29. The compound ofclaim 1 wherein said pharmaceutically acceptable salt is selected fromthe group consisting of hydrobromide, hydrochloride, sulfate, bisulfate,nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate,laurate, borate, benzoate, lactate, phosphate, tosylate, citrate,maleate, fumarate, succinate, tartrate, naphthylate, mesylate,glucoheptonate, lactiobionate, and laurylsulfonate.
 30. A pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of compound having histamine H₃receptor modulator activity of formula (I):

wherein R¹, optionally mono- or di-substituted with R^(s), is selectedfrom the group consisting of —H, —C₁₋₇alkyl, —C₂₋₇alkenyl, —C₂₋₇alkynyl,and —C₃₋₇cycloalkyl; R^(s) is independently selected from the groupconsisting of —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₃₋₆cycloalkyl, phenyl,pyridyl, furanyl, thienyl, benzyl, pyrimidinyl, pyrrolyl, halo, —OH,—OC₁₋₆alkyl, —OC₃₋₆cycloalkyl, -Ophenyl, -Obenzyl, —SH, —SC₁₋₆alkyl,—SC₃₋₆cycloalkyl, -Sphenyl, -Sbenzyl, —CN, —NO₂, —N(R^(m))R^(n) (whereinR^(m) and R^(n) are independently H or C₁₋₄alkyl), —(C═O)N(R^(m))R^(n),—(C═O)C₁₋₄alkyl, —SCF₃, —OCF₃, —CF₃, —COOC₁₋₄alkyl, and —COOH; n is 1 or2; X is O or S; the A-containing ring is thiophene; L is —C₁₋₄alkylene-;R², optionally mono- or di-substituted with R^(q) is independentlyselected from the group consisting of —H, —C₁₋₇alkyl, —C₂₋₇alkenyl,—C₂₋₇alkynyl, —C₃₋₇cycloalkyl, phenyl, benzyl, pyridinyl, pyrimidinyl,furanyl, thienyl, pyrrolyl, and a 5-, 6-, or 7-membered monocyclicnon-aromatic heterocyclic ring having 1 or 2 heteroatom members selectedfrom O, S, —N═, >NH, and >NC₁₋₄alkyl, having 0, 1, or 2 double bonds;and R³, optionally mono- or di-substituted with R^(q), is independentlyselected from the group consisting of —C₁₋₇alkyl, —C₂₋₇alkenyl,—C₂₋₇alkynyl, —C₃₋₇cycloalkyl, phenyl, benzyl, pyridinyl, pyrimidinyl,furanyl, thienyl, pyrrolyl, and a 5-, 6-, or 7-membered monocyclicnon-aromatic heterocyclic ring having 1 or 2 heteroatom members selectedfrom O, S, —N═, >NH, and >NC₁₋₄alkyl, having 0, 1, or 2 double bonds;R^(q) is independently selected from the group consisting of —C₁₋₆alkyl,—C₂₋₆alkenyl, —C₃₋₆cycloalkyl, phenyl, pyridyl, furanyl, thienyl,benzyl, pyrimidinyl, pyrrolyl, halo, —OH, —OC₁₋₆alkyl, —OC₃₋₆cycloalkyl,-Ophenyl, -Obenzyl, —SH, —SC₁₋₆alkyl, —SC₃₋₆cycloalkyl, -Sphenyl,-Sbenzyl, —CN, —NO₂, —N(R^(y))R^(z) (wherein R^(y) and R^(z) areindependently selected from H and C₁₋₄alkyl; or R^(y) and R^(z) may betaken together with the nitrogen of attachment to form a 5-, 6-, or7-membered monocyclic heterocyclic ring having 1 or 2 additionalheteroatom members selected from O, S, —N═, >NH, and >NC₁₋₄alkyl, saidring optionally substituted with halo or —C₁₋₄alkyl),—(C═O)N(R^(y))R^(z), —(C═O)C₁₋₄alkyl, —SCF₃, —OCF₃, —CF₃, and—COOC₁₋₄alkyl, and —COOH; or, alternatively R² and R³ may be takentogether with the nitrogen of attachment to form a ring, said ringselected from the group consisting of: i) a 4-7 membered non-aromaticheterocyclic ring said heterocyclic ring having 0 or 1 additionalheteroatom members separated from the nitrogen of attachment by at leastone carbon member and selected from O, S, —N═, >NH, and >NR¹¹, having 0,1, or 2 double bonds, having 0, 1, or 2 carbon members which is acarbonyl, having 0, 1, or 2 substituents R^(p); and ii) a benzo orpyrido fused 4-7 membered non-aromatic heterocyclic ring saidheterocyclic ring having 0 or 1 additional heteroatom members separatedfrom the nitrogen of attachment by at least one carbon member andselected from O, S, —N═, >NH, and >NR^(pp), having 0 or 1 additionaldouble bonds, having 0, 1, or 2 carbon members which is a carbonyl, andhaving 0, 1, or 2 substituents R^(p); R^(p) is independently selectedfrom the group consisting of —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₃₋₆cycloalkyl,phenyl, pyridyl, furanyl, thienyl, benzyl, pyrimidinyl, pyrrolyl, halo,—OH, —OC₁₋₆alkyl, —OC₃₋₆cycloalkyl, -Ophenyl, -Obenzyl, —SH,—SC₁₋₆alkyl, —SC₃₋₆cycloalkyl, -Sphenyl, -Sbenzyl, —CN, —NO₂,—N(R^(y))R^(z) (wherein R^(y) and R^(z) are independently selected fromH and C₁₋₁₄alkyl; or R^(y) and R^(z) may be taken together with thenitrogen of attachment to form a 5-, 6-, or 7-membered monocyclicheterocyclic ring having 1 or 2 additional heteroatom members selectedfrom O, S, —N═, >NH, and >NC₁₋₄alkyl, said ring optionally substitutedwith halo or —C₁₋₄alkyl), —(C═O)N(R^(y))R^(z), —(C═O)C₁₋₄alkyl, —SCF₃,—OCF₃, —CF₃, —COOC₁₋₄alkyl, and —COOH; R^(pp) is independently selectedfrom the group consisting of —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₃₋₆cycloalkyl,phenyl, pyridyl, benzyl, pyrimidinyl, pyrrolyl, —(C═O)N(R^(y))R^(z),—(C═O)C₁₋₄alkyl, —COOC₁₋₄alkyl, and —COOC₁₋₄benzyl; and enantiomers,diastereomers, hydrates, solvates and pharmaceutically acceptable salts,esters and amides thereof. 31-32. (canceled)
 33. A compound of claim 1isotopically-labelled to be detectable by PET or SPECT.
 34. A method forstudying histamine-mediated disorders comprising the step of using an¹⁸F-labeled or ¹¹C-labelled compound of claim 1 as a positron emissiontomography (PET) molecular probe. 35-37. (canceled)